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Published on: February 16, 2020
The effect of HMGB1, a damage-associated molecular pattern molecule, on polymorphonuclear neutrophil migration
Florence Berthelot1, Lakhdar Fattoum, Sarah Casulli
1Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872 et Université Paris Descartes, UMR S 872, INSERM, Paris, France.
Abstract:
Polymorphonuclear neutrophils (PMN) play a key role in host defenses against invading microorganisms but also potentiate inflammatory reactions in case of excessive or misdirected responses. Release of the alarmin high-mobility group box 1 (HMGB1) by cells that die at an inflammatory site may act as an alert signal for the immune system. We studied the effect of HMGB1 on human PMN migration, using whole-blood samples to avoid cell activation associated with isolation procedures. HMGB1 50-100 ng/ml reduced baseline PMN migration as well as formyl-methionyl-leucyl-phenylalanine- and IL-8-induced PMN chemotaxis. This inhibitory effect was mediated by the RAGE receptor. In contrast, a higher HMGB1 concentration (5,000 ng/ml) had a chemoattractant effect on PMN through IL-8 production. This effect required the engagement of Toll-like receptors 2 and 4 in addition to the RAGE receptor. The A box component of HMGB1, which antagonizes the endogenous protein, reduced chemotaxis and also strongly inhibited the enhancement of PMN migration observed with the highest HMGB1 concentration. In contrast, the B box, reported to be the active form of HMGB1, exerted a chemoattractant effect. These results strongly point to a key regulatory role of HMGB1 in PMN recruitment to inflammatory tissues. The A box component could potentially serve to inhibit inappropriate PMN recruitment during chronic inflammatory disorders associated with excessive HMGB1 release.
Insights
High-mobility group box 1 (HMGB1) regulates polymorphonuclear neutrophil (PMN) migration. HMGB1 can inhibit or attract PMNs depending on concentration, offering potential therapeutic strategies for inflammatory diseases.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Polymorphonuclear neutrophils (PMNs) are crucial for host defense but can exacerbate inflammation.
- High-mobility group box 1 (HMGB1), an alarmin released during cell death, signals immune responses.
- Understanding HMGB1's role in PMN behavior is vital for managing inflammatory conditions.
Purpose of the Study:
- To investigate the dual effect of HMGB1 on human PMN migration.
- To elucidate the receptor pathways involved in HMGB1-mediated PMN responses.
- To explore the distinct roles of HMGB1's A and B boxes in PMN recruitment.
Main Methods:
- Studied human PMN migration in whole-blood samples to preserve native cell states.
- Utilized varying concentrations of HMGB1 (50-100 ng/ml and 5,000 ng/ml) to assess dose-dependent effects.
- Investigated the involvement of RAGE, Toll-like receptors 2 and 4, and HMGB1's A and B boxes.
Main Results:
- Low HMGB1 concentrations (50-100 ng/ml) inhibited PMN migration via RAGE.
- High HMGB1 concentration (5,000 ng/ml) chemoattracted PMNs by inducing IL-8 production, involving RAGE, TLR2, and TLR4.
- HMGB1's A box inhibited PMN chemotaxis, while the B box promoted it.
Conclusions:
- HMGB1 exhibits a concentration-dependent, dual role in regulating PMN recruitment to inflammatory sites.
- HMGB1's distinct domains (A and B boxes) mediate opposing effects on PMN migration.
- The HMGB1 A box may offer a therapeutic target to control excessive PMN recruitment in chronic inflammatory disorders.
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